Muscarinic M1, M3, Nicotinic,GABAA and GABAB Receptor ...

110
Discussion
brain for learning, basal ganglia for reinforcement learning and cerebral cortex for
unsupervised learning (Doya, 1999). There is increasing evidence that the
cerebellum is involved in cognition, behaviour and emotion (Schmahmann &
David, 2006). Cerebellar dysfuncton is associated with poor fine motor skills,
hypotonia (Wassmer et al., 2003). Studies from our laboratory have demonstrated
that cerebellum is susceptible to hypoglycemia (Joseph et al., 2007, 2008).
Gene expression studies showed that the mRNA level of muscarinic M1
and M3 receptors in the cerebellum of hypoglycemic rats substantially increased
compared to diabetic and control. Also, the binding parameters Bmax of total
muscarinic, muscarinic M1 and M3 receptors were increased in experimental rats.
Immunohistochemical study using confocal microscope confirmed a similar
expression pattern in localization of muscarinic M1, M3 receptors in the
cerebellum of experimental rats. Our results showed that cholinergic transmission
mediated through muscarinic receptors in the cerebellar circuitory is affected
during diabetes and exacerbated by recurrent hypoglycemia increasing the
susceptibility of cerebellar purkinje cells to neuronal damage. The cellular basis
of motor learning has been mostly attributed to long term depression (LTD) at
excitatory parallel fiber - purkinje cell synapses. LTD is induced when parallel
fibers are activated in conjunction with a climbing fiber, the other excitatory input
to Purkinje cells. The cerebellum has generally been suggested to be involved in
the control and integration of motor processes, as well as cognitive functions.
Synaptic ACh levels are known to be regulated by the activity of presynaptic
muscarinic autoreceptors mediating inhibition of ACh release. In terms of the
contribution of cholinergic cerebellar abnormalities to mental function, early
reports of cerebellar abnormalities in autism (Courchesne, 1995) and of
intellectual and behavioural abnormalities in patients with cerebellar damage
(Botez-Marquard, 2001) originally suggested a cognitive role for the cerebellum.
Since then, many studies have confirmed that the cerebellum contributes to
cognitive and other non-motor functions. These neurofunctional deficits are one